Diabetic retinopathy (DR) remains the most common cause of vision impairment in working-age adults in the United States and Europe, and retinal neovascularization occurs in up to 20% of patients with diabetes. The current treatment of ablating the peripheral retina, while effective in reducing the risk of severe vision loss, is only applied after the onset of neovascularization, does not address the basic biological abnormality that leads to this complication, reduces peripheral and night vision, and is uncomfortable and expensive. So far, there is no clinically proven non-surgical alternative. Anti-VEGF therapies, which are already used to treat ocular neovascularization in age-related macular degeneration (AMD), raise concerns for diabetic patients; antagonism of VEGF might interfere with myocardial revascularization in patients who are already at high risk for cardiac ischemia, for example, and loss of the neurotrophic and vasculotrophic actions of VEGF might exacerbate neuronal loss and ischemia in diabetic eyes. Therapies that address the multifactorial nature of retinopathy will probably be more successful than single-molecule-specific approaches (Gariano & Gardner, Nature 438, 960-966, 2005).
Pathological retinal neovascularization in patients with diabetes results from an imbalance of pro-angiogenic and anti-angiogenic factors. In addition to VEGF accumulation in eyes with diabetic retinal neovascularization, changes in numerous other cytokines, chemokines, adhesion molecules, vasoactive hormones and immune cells have been reported. Together, these changes constitute a complex inflammatory process that results in an aberrant wound-healing response. Recent work shows that all retinal cell types, including neurons, glial, microglial and vascular cells, are affected by diabetes, resulting in a neurovascular disorder. The retinal neurovascular degeneration of diabetes includes neuronal and vascular cell apoptosis, and microglial and glial cell activation, which provides intraretinal sources of cytokines and chemokines (Gariano & Gardner, Nature 438, 960-966, 2005).
Clinically, diabetic retinopathy (DR) is classified into two stages: non-proliferative DR (NPDR) and proliferative DR (PDR). In NPDR, VEGF-A (which is known to act as a survival factor for endothelial cells, via induction of anti-apoptotic proteins) expression in elevated levels has been described in human and in experimental models of DR. VEGFRs are also upregulated in NPDR. VEGF-A may be increased initially in preclinical DR as a mechanism to maintain the integrity of the retinal vascular bed. In a later stage, high VEGF-A production in ischemic areas, where VEGFR-2 is upregulated, then leads to vascular leakage and neovascularisation. In proliferative DR (PDR), intra-ocular neovascularisation is likely caused by high levels of VEGF-A in the vitreous derived from widespread production of this factor by ischemic retina. Elevated levels of VEGF-A have been found in the aqueous humor and vitreous of patients with PDR (Witmer et al., Prog Ret Eye Res 22, 1-29, 2003).
Age-Related Macular Degeneration (AMD) is one of the leading causes of irreversible vision loss in the Western world, accounting for 75% of legal blindness in the population of age 50 years old or older in the developed countries (Zhang & Ma, Prog Ret Eye Res 26, 1-37, 2007).
Two subgroups of AMD are classically distinguished: atrophic (dry form) and exudative (wet form). The dry form (also known as geographic atrophy, both central and/or non-central) is typically characterized by a progressing course leading to degeneration of retinal pigment epithelium (RPE) and photoreceptors. The exudative form is linked to choroidal neovascularization (CNV, the abnormal growth of blood vessels that originate from the choroidal vasculature) directed to the subretinal macular region, with subsequent bleeding and/or fluid leakage, which may result in a sudden loss of central vision; it is the most rapidly progressing form of AMD. Clinical features common for the two types of AMD include the presence of drusen, which is defined as the complex deposits of lipids, proteins, and inflammatory mediators that develop in the Bruch's membrane under the RPE, as well as hypo- and/or hyperpigmentation of the RPE. More than 80% of all people with intermediate and advanced AMD have the dry form, yet this form may progress to the wet form which leads to significantly more vision loss (Zhang & Ma, Prog Ret Eye Res 26, 1-37, 2007; Nowak, Pharmacol Reports 58, 353-363, 2006).
The pathophysiology of AMD is complex and, in addition to genetic predispositions, at least four processes contribute to the disease, i.e. lipofuscinogenesis (with its linkage to oxidative stress), drusogenesis, local inflammation and neovascularization (in the case of wet form). In order to stimulate the process of angiogenesis, including CNV, the angiogenesis-linked molecular machinery must be disbalanced in a way promoting functional overactivity of pro-angiogenic signaling. This may result from either an unbalanced increase in pro-angiogenic (e.g. VEGF) activity or an unbalanced decrease in anti-angiogenic (e.g. pigment epithelium derived factor, PEDF) activity. Despite many similarities in the pathways leading to the retinal and choroidal neovascularization, there are some major differences between these two types of angiogenesis. Current view suggests that in the initiation and development of CNV, there may be a role for local inflammation together with immune reactions as a process creating cellular and molecular milieu promoting the prevalence of pro-angiogenic mechanisms; in fact, neutrophils, macrophages, mast cells, activated microglia, all are capable of producing and releasing an array of pro-angiogenic factors, including VEGF. Recent findings confirm the role of VEGF and PEDF as important regulators engaged in CNV, and this fact has already its impact on establishing therapeutic strategies to combat the existing or to prevent the development of newly formed unwanted blood vessels (Nowak, Pharmacol Reports 58, 353-363, 2006).
In patients with AMD, high levels of VEGF and VEGF receptor have been detected in the subfoveal fibrovascular membrane, the surrounding tissues and the RPE (Zhang & Ma, Prog Ret Eye Res 26, 1-37, 2007).
Thus, there remains a need for safe, effective, non-invasive and inexpensive compositions and methods to treat and/or prevent various ophthalmic and ocular disorders, such as DR and AMD. The present invention provides such methods and compositions.